Benzofuranes and their use in the treatment of atrial fibrillation

ABSTRACT

This intention relates to new compounds and their pharmaceutical use, and to the pharmaceutical use of known compounds, which compounds inhibit certain transmembrane potassium currents in the atrium of the heart of a mammal without significantly affecting other ion channels, for the treatment of heart disease particularly atrial fibrillation. The invention also relates to pharmaceutical compositions comprising such compounds.

FIELD OF THE INVENTION

This invention relates to novel compounds that inhibit certaintransmembrane potassium currents in the atrium of the heart of a mammalwithout significantly affecting other ion channels. It also relates tothe use of certain known compounds in the, preparation of a medicamentfor the treatment of heart diseases, particularly atrial fibrillation.It further relates to pharmaceutical compositions containing compoundsthat inhibit certain transmembrane potassium currents in the atrium ofthe heart of a mammal without significantly affecting other ionchannels, for the treatment of heart disease, particularly atrialfibrillation.

BACKGROUND OF THE INVENTION

Cell membranes have a basic lipid bilayer structure that is impermeableto ions. Special proteins (hereafter referred to as ion-channels) haveevolved that provide pathways for ions to cross cell membranes and somake the membrane permeable to ions, such as potassium (hereafter K), assodium (hereafter Na) or calcium (hereafter Ca). Opening and closing ofion-channels make the membrane permeable or impermeable to differentions and thereby they regulate many properties and functions of the cellmembrane. Ion-channels enable cells to set up membrane potentials, andallow currents to flow that change these membrane potentials, therebyunderlying electrical signaling by the cell membrane. A transmembranecurrent (hereafter I) is the ion-flow through an open ion-channel.Ion-channels are targets for many antiarrhythmic drugs, which are usedto treat abnormal electrical activity in the heart. From a therapeuticperspective, blocking of K-channels prolongs the action potentialduration (APD) and lengthens the refractory period, and is a classicalantiarrhythmic mechanism generating a Q-T prolongation on the surfaceECG (Singh B and Nademanee K, Am Heart J, 1985, 109:421-30).

Several different kinds of ion-channels, including Na— Ca— and K— ionchannels, are active in the mammalian heart giving rise to differention-currents (e.g. INa, ICa and IK). Most K-channels are either voltageactivated such as the Delayed Rectifier K-channel (resulting in thecurrent IK), the Transient Outward K-channel (resulting in the currentIto) or ligand operated such as the ATP-sensitive K-channel which isopened during metabolic impairment (when intracellular levels of ATP arereduced) which generates the current IK(ATP). Another ligand-activatedK-channel is the Muscarinic K-channel which is activated whenacetylcholine binds to the muscarinic receptor M2 (resulting in thecurrent IK(ACh) or when adenosine binds to the adenosine receptor A1 inthe current IK(Ado).

Antiarrhythmic drugs are grouped according to their essential inhibitoryeffects on certain ion-currents; class I drugs predominantly inhibitsodium currents and class III drugs predominantly inhibit potassiumcurrents. However, antiarrhythmic drugs that are used today are notselective in their ion-channel blocking and every drug used todayinteracts with several currents.

K-channel blocking in the heart may be one of the most efficientantiarrhythmic mechanisms identified so far. The problem is that anydrug that prolongs repolarization has an intrinsically associated riskof inducing torsade de points arrhythmia in the ventricle. However,since the K-channels responsible for repolarization actually differbetween the atrium and the ventricle, it is possible to identifyK-channels that will be active against supraventricular arrhythmias butthat will not prolong the QT-interval and thus will not beproarrhythinic.

Blocking of the particular ligand-activated K-currents IK(Ado) and/orIK(ACh) has been shown to occur with anti-arrhythmic agents. It has alsobeen postulated that this mechanism may be of importance in explainingthe efficacy of anti-arrhythmic drugs for the treatment of atrialfibrillation (Mori K, et al. Circulation 1995 Jun. 1;91(11):2834-43;Ohmoto-Sekine Y, et al. Br J Pharmacol 1999 February;126(3):751-61;Watanabe Y, et al. J Pharmacol Exp Ther 1996 November;279(2):617-24).The ligand-gated currents IK(Ado), IK(ACh) and Il((ATP) probably onlyhave minor roles in shaping repolarization under normal conditions but,when activated by extracellular acetylcholine, by extracellularadenosine or reduction of intracellular ATP concentrations respectively,these currents are increased and thus can substantially shorten theaction potential duration (APD) (Belardinelli L, et al. FASEB J 1995;9(5):359-365; Belardinelli L and Isenberg G. Am J Physiol 1983;244(5):H734-H737; Findlay I and Faivre J F. FEBS Lett 1991;279(1):95-97). The therapeutic effect of anti arrhythmic agents is toprolong APD and thereby make the atrial myocardium more refractive toabnormal electrical activity.

It is expected that the ligand-gated channels IK(Ado) and IM(ATP)are-more active in atrial tachyarrhythmias (i.e. atrial fibrillation(AF) and atrial flutter) than in normal sinus-rhythm, whereas IK(ACh),activation is dependent on vagal activity (presynaptic release of ACh).Atrial consumption of ATP is increased in atrial tachyarrhythmiasleading to increased levels of adenosine (a metabolite of ATP)activating IK(Ado) and leading to reduced intracellular ATPconcentration, hence, activating IK(ATP) (Asheroft S J and Ashcroft F M.Cell Signal 1990; 2(3):197-214).

Atrial fibrillation is today seldom treated with antiarrhythmic agentsto normalize the abnormal electric activity. The primary reason for thereluctance to treat AF-patients with drugs that effectively normalizeatrial electric activity is that available anti-arrhythmic drugs alsoblock other ion-channels, in addition to the ligand-gated channelsIK(Ado), IK(ACh) and IK(ATP), in the heart. Therefore, treatment ofAF-patients with currently-available anti-arrhythmic drugs is associatedwith a substantial risk to induce lethal proarrhythmic effects (asTorsade-de Points in the ventricle); It is of importance to considerthat the antiarrhythmic agents referenced in Table 1 are not exclusivelyactive on the ligand-gated currents IK(Ado), IK(ACh) and IK(ATP), butalso block other transmembrane currents (references in Table 2).

The class III-agent amiodarone has been shown to be effective fortreatment of AF (Roy D, et al., N Engl J Med 2000 Mar.30;342(13):913-20) and indeed aniodarone does block ligand-gatedcurrents IK(Ado) and IK(ACh) (Watanabe Y, et al. supra). However, inspite of the proven efficacy of amiodarone to treat AF, the side effectprofile of the drug is complex; there are features such as pulmonarytoxicity, ocular and skin changes, and other forms of organ toxicitythat clearly limit its widespread clinical utility (Pollak, T. M. Am. J.Cardiol., 1999, 84, 37R-45R; Wiersinga, W. M. Chapter 10, Amiodarone andthe Thyroid, In Handbook of Experimental Pharmacology, Weetman A. P.,Grossman, A., Eds.; Springer-Verlag.: Berlin, Heidelberg, 1997, Vol128). Amiodarone has a complex pharmacokinetic profile and theelimination of the drug is extremely slow (Wiersingha, supra). In spiteof its proven efficacy for treatment of AF, amiodarone is not frequentlyused as a treatment due to all side effects associated with its use. Anovel anti-arrhytmic drug which shares the inhibitory effect on theligand activated currents IK(Ado)/IK(ACh) with amiodarone but displayslower organ toxicity than that drug would provide an improved treatmentfor AF. Indeed, data from toxicological studies performed with compoundsof the, present invention or used in the present invention suggest areduced toxicity as compared to amiodarone. The extreme pharmacokineticbehavior amiodarone complicates dosing of that drug and thus it would beof great clinical benefit to have a drug which shares the inhibitoryeffects on the; ligand activated currents IK(Ado)/IK(ACh)/IK(ATP) withamiodarone but that displays mainstream pharmacokinetics. Data fromblood pharmacokinetics, tissue distribution and mass balance studies oncompounds used in the present invention indicates that the clinical useof these compounds will be less complicated than that of amiodarone. Anideal drug for treatment of atrial fibrillation should also selectivelyinhibit the atrial currents that are increased under the pathologicalconditions characterizing the disease and lack effects on othercurrents. This is the case with the compounds of the present inventionsince the IK(Ado)/ATP current is predominantly active in thefibrillating atrium and the IK(ACh) is the current responsible for theinduction of vagal-triggered atrial fibrillation. In comparison withother antiaarhythmic drugs (see table 2) the compounds of the presentinvention are essentially free from interactions with other ion-currentsand can therefore be regarded as selective inhibitors of the K-currents(IK(Ado), IK(ACh) and IK(ATP)) that have an increased activity insupraventricular cardiac arrhytmias (i.e. atrial fibrillation) butwithout the ability to block the ion-currents that mediate electricalactivity in the cardiac ventricles and in the normal atrium.

Both the compounds that are the subject of the present invention andamiodarone have been shown to antagonize triiodthyronine (T3)-signallingaction in cells (manuscript in preparation) and therefore it should benoted that the inhibitory effects seen with such compounds on IK(Ado),IK(ACh) and IK(ATP)) are not due to T3-antagonism. There are twofindings that support this statement; a) T3 does not have acute effectson IK(Ado) or IK(ACh) and b) potent T3-antagonists (100× more potentthan the compounds that are the subject of the present invention onT3-receptor mediated signaling) do not display similar acute effects onIK(Ado) or IK(ACh).

DESCRIPTION OF THE INVENTION

In the present invention acute and chronic effects of various compoundshave been investigated by using electrophysiology technique applied tocardiomyocyte cultures. The inventions have found that certain compoundsinhibit transmembrane K-currents that are induced through stimulation bymuscarinic receptor agonists such as AcetylCholine (ACh) or A1 adenosinereceptor agonists such as Adenosine (Ado) and by reduction ofintracellular ATP.

The inhibitory effects occur within seconds after induction of thecurrent with ACh, Ado or dinitrophenole (DNP reduces intracellular ATP).The acute inhibitory effects caused by the compounds of the presentinvention on these K-currents in cardiac muscle tissue had notpreviously been discovered. The reasons for this include the fact thatthese ligand activated K-currents (IK(Ado), IK(ACh) and IK(ATP)) arepreferentially active in the atrial cardiomyocytes (Workman A J et al.Cardiovasc Res 1999 September;43(4):974-84; Koumi S-I, and WasserstormA. American Journal of Physiology 266[35], H1812-H1821. 1994), whileprevious studies have been carried out with tissue from cardiacventricles. Furthermore, IK(Ado) and IK(ACh) must first be induced viathe M2 or A1 receptor (with ACh and Ado respectively) before anyinhibition can be observed. Without any agonist at the extracellularsite of the membrane these ligand-gated channels probably have onlyminor roles in shaping repolarization but, when activated byextracellular acetylcholine or adenosine, they can substantially shortenaction potential duration in the atrium (Tristani-Firouzi M et al. Am JMed 2001 January; 110(1):50-9).

Similar effects (i.e. inhibition of IK(Ado) or IK(ACh)) have beendescribed for other antiarrhythmic drugs such as: E-4031, and MS-551(Mori et al. supra), aprinidine (Ohmoto et al. supra) Amiodarone(Watanabe et al. supra) and terikalant (Brandts B. et al. Pacing ClinElectrophysiol 2000 November;23(11 Pt 2):1812-5); see Table 1.

One aspect of the invention is that compounds that are able to block oneor both of the K-currents IK(Ado) and IK(ATP) should be efficient aspharmacological treatments for atrial fibrillation and/or atrialflutter.

It is wells known that prolonged atrial fibrillation facilitates hepersistence and/or reoccurrence of arrhythmia (Wijffels M. et al.Circulation 92, 1954-1968. 1995). The pathophysiological background ofthis observation is the alteration of ion channel expression in atrialmyocytes (electrical remodeling; Yue L. et al. Circulation Research 81,512-525. 1997; Yue L. et al. Circ Res 1999; 84(7):(776-784). Seeking forstrategies to treat atrial fibrillation one has to appreciate the factthat electrical remodeling is not the primary cause of the arrhythmia.Electrical remodeling is, a phenomenon that develops in patients and inthe healthy heart. Other mechanisms than electrical remodeling aresuggested to be responsible for the development of the “disease atrialfibrillation”. These mechanisms are discussed to be relevant at theearly phase of the arrhythmia (a few minutes to a few hours).

The high frequency activation of the atrial myocardium during atrialfibrillation (more than 5 Hz) is suggested to significantly increaseatrial oxygen consumption and thereby to significantly increaseintracellular and interstitial adenosine concentrations due tointracellular loss of ATP. These mechanisms have been well described forventricular fibrillation (Weiss J N et al. J Physiol 1992; 447:649-673;Schrader J. et al. Experientia 1990; 46(11-12):1172-1175; Decking U K etal. Circ Res 1997; 81(2):154-164; Deussen A. and Sclirader J. J Mol CellCardiol 1991; 23(4):495-504). Due to methodical difficulties at theatrial level (much less tissue, no option to selectively collect atrialeffluate) only indirect observations suggest the occurrence of ischaemiaduring atrial fibrillation. After episodes of atrial fibrillation Daodet al. showed a reduction of atrial effective refractory period whichwas abolished after some tens of seconds during sinus rhythm (Daoud E Get al. Circ 1996; 94:1600-1606). Furthermore Rubart et al. showedelevated potassium concentrations during AF (Rubart M. et al. JCardiovasc Electrophysiol 2000; 11 (6):652-664). Both observations fitvery well with the hypothesis of atrial fibrillation-induced ischaemiain the atria. The consequence of atrial ischaemia during atrialfibrillation would be the activation of IK(Ado) and IK(ATP). Bothcurrents are known to markedly reduce the atrial effective refractoryperiod. A reduction of this period however is known to be one majordeterminant for the development of reentry tachycardias like atrialfibrillation. Since inhibition of IK(ATP) and IK(Ado) could reverse theshortening of the atrial effective refractory period such an inhibitionis expected to be of significant pharmacological value in the treatmentof atrial fibrillation. Moreover, since the ventricular tissue isactivated at a “normal” rate during atrial fibrillation IK(Ado) andIK(ATP) are not expected to be active. Hence a drug which selectivelyinhibits IK(Ado) and IK(ATP) will not influence ventricularelectrophysiolgy, and hence will not exert dangerous proarrhythmiceffects. Furthermore, as mentioned above, IK(Ado) is much less expressedin ventricular myocytes.

Another aspect of the invention is the fact that compounds that are ableto block. IK(ACh) should be efficient as pharmacologial treatments for adefined subgroup of patients in which the pathophysiology of atrialfibrillation has been well defined: Vagal-induced atrial fibrillation isregarded as an arrhythmia occurring when an increased vagal activityreduces the atrial effective refractory period by activation of IK(ACh).Because adenosine- and acetylcholine-induced inward rectifying potassiumcurrent is represented by the activation of the same ion channelpopulation (Bünemann M. et al. J Physiol (Lond) 1995; 489(3):701-707;Bünemann M. et al. EMBO 1996), an inhibitor of adenosine-activated ionchannels will also be an effective inhibitor of IK(ACh). Inhibition ofIK(ACh) would be of significant value for the treatment of vagal-inducedatrial fibrillation.

There is a unique specificity of the compounds that are the subject ofthe invention to exclusively block the three currents IK(ACh), IK(Ado),and IK(ATP). Several compounds that display well-known anti-arrhythmicproperties have been shown to inhibit at least one of these threecurrents (see Table 2). However, all these other compounds are known toinhibit other ion-currents as well. Table 2 is a compilation ofantiarrhythmic drugs that have been shown to inhibit IK(ACh).Interestingly compounds from different classes of antiarrhythmiccompounds have all been shown to display similar actions on thisparticular current and the compilation includes “second generation”class III antiarrhythmic compounds, such as D-sotalol and Terikalant,which are potent inhibitors of the rapid component of delayed rectifyingK-current (IKr). The compilation also includes the class III agentsAmiodarone and Dronedarone that are known to inhibit severaltransmembrane currents (i.e Ca-currents) in addition to the currentslisted in table 2. Also class I antiarrhythmic drugs as Flecainide,Quinidine, Disopyramide and Aprinidine are included. The most prominentmechanisms of antiarrhythmic activity of these class I compoundsblockade of inward Na-currents.

Results from voltage clamp experiments with compounds of the inventionon other ion-currents than IK(Ado), IK(ACh) and IK(ATP) are included inTable 2. Data from these voltage-clamp experiments demonstrate theabsence of any relevant inhibition of the currents IK1, IKs, INa and Itoby compounds of the present invention.

The unique selectivity of the compounds that are the subject of thepresent invention to solely inhibit IK(ACh), IK(Ado), and IK(ATP)suggests that they will be effective in the treatment of atrialfibrillation and/or atrial flutter to normalize pathological electricactivity in the atrium. The absence of inhibition of other ion-currentssuch as the inward rectifier (IK1), the slow component of the delayedrectifier (IKs), the transient outward K-current (Ito) or thedepolarizing Na-current (INa) predict the risks for the compounds of thepresent invention to induce proarrhytmicity in normal cardiac tissue tobe minor. Today clinicians are reluctant to treat AF-patients witheffective antiarrhythmic drugs due to the intrinsic risks ofproarrhythmic effects in the ventricles associated with thecurrently-available drugs. The selective action of the compounds of thepresent invention excludes significant effects on ventricularelectrophysiology yielding prevention of proarrhythmias at that level.Moreover, the pharmacodynamic profile of the compounds of the presentinvention is expected to be of special value for the treatment of everykind of atrial fibrillation (inclusive of vagal-induced atrialfibrillation) without ventricular proarrhythmias.

Another aspect of the invention is that the compounds that it isconcerned with are at least as potent as the drug amiodarone as blockersof the currents IK(Ado), IK(Ach) and IK(ATP) and this aspect togetherwith the available safety documentation on the compounds of the presentinvention, suggesting an apparently much better safety profile than whatis seen with amiodarone, indicates that the compounds of the presentinvention will be at least as efficaceous as amiodarone for treatment ofAF but with fewer adverse effects.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with a first, of the present invention, novel compoundsare provided that inhibit certain transmembrane K-currents that areinduced through stimulation by muscarinic receptor agonists such asAcetylCholine (ACh) or A1 adenosine receptor agonists such as Adenosine(Ado) and by reduction of intracellular ATP.

Consequently, in a first aspect of the invention there are providedcompounds according to the general formula I:

wherein;

-   R₁ is C₁-C₄ alkyl;-   R₂ is NHCOR^(a), NHCONHR^(a), or hydrogen;-   R₃ and R are independently selected from fluorine, chlorine, C₁-C₆    alkyl, and CF₃;-   R^(a) is selected from CF₃, C₁₋₃ alkyl, and -(4-R^(b))C₆H₄;-   R^(b) is selected from C₁₋₄ alkoxy, hydroxy, fluoro, and nitro;-   R₅ is selected from hydrogen and —CH₂—COOH;-   X is selected from CH₂ and C═O; with the proviso that when R₅ is    hydrogen, X is —CH₂—;    and pharmaceutically acceptable salts, esters and isomers thereof.

Preferably R₂ is hydrogen. Also preferably, where R₂ is H or NHCOR^(a),R₃ and R₄ are independently C₁-C₄ alkyl, and more preferably R₃ and R₄are both isopropyl.

In compounds where R₅ is —CH₂—COOH, R₁ is preferably methyl; R₂ ispreferably hydrogen; R₃ and R₄ are preferably independently C₁-C₄ alkyl;R₅ is preferably —CH₂—COOH; and X is preferably —CH₂—.

Especially preferred compounds of the invention are:

-   2-methyl-3-(3,5-diisopropyl-4-hydroxybenzoyl)benzofuran (E1);-   2-methyl-3-(3,5-diisopropyl-4-carboxymethoxybenzoyl)benzofuran (E2);-   2-methyl-3-(3,5-diisopropyl-4hydroxybenzyl)benzofiuran (E3);-   2-methyl-3-(3,5-diisopropyl-4carboxymethoxybenzyl)benzofuran (E4);    and pharmaceutically acceptable salts and esters thereof and isomers    thereof.

In accordance with a second aspect of the invention there is provided apharmaceutical use of a compound that inhibits certain transmembranepotassium current, which are more active in the diseased atrium of amammalian heart than in a normal atrium, without affecting other ionchannels, for the preparation of a medicament for the treatment orprevention of atrial fibrillation and atrial flutter. Preferably thesaid inhibition derives from inhibition of one or several of the threeligand-sensitive potassium currents IK(Ado), IK(ACh) and IK(ATP). Theinhibition caused by the said compound is more preferably not due to aT3 antagonistic effect.

The said compounds are described by the general formula II:

wherein;

-   R⁶ is C₁-C₄ alkyl;-   R⁷ is NHCOR¹⁰, NHCONHR¹⁰, or hydrogen;-   R⁸ and R⁹ are independently selected from iodine, and bromine;-   R¹⁰ is selected from CF₃, C₁-C₃ alkyl, and (4-R¹¹)C₆H₄;-   R¹¹ is selected from C₁-C₄ alkoxy, hydroxy, fluoro, and nitro;-   R¹² is selected from hydrogen, and CH₂—COOH;-   X is selected from CH₂ and C═O;    or pharmaceutically acceptable salts and esters thereof and isomers    thereof.

Preferably, the compound of formula II is selected from:

-   2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran (E5);-   2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran (E6);    and pharmaceutically acceptable salts, esters, and isomers thereof.

Another embodiment of the present invention relates to pharmaceuticalcompositions for the treatment of atrial fibrillation or atrial fluttercomprising at least one compound of formula I or II, if appropriatetogether with a pharmaceutically-acceptable carrier.

Yet another embodiment of the present invention relates to a method oftreating atrial fibrillation or atrial flutter comprising providing to apatient in need thereof a O: pharmaceutically effective amount of atleast one compound of formula I or I.

The synthesis and detailed description of the compounds of formula IIare described in WO 96/0510 and WO 92/20331.

The compounds of formula I and formula II can be used in combinationwith other agents ti useful for treating atrial fibrillation and atrialflutter. The individual components of such combinations can beadminister separately at different times during the course of therapy ora concurrently in divided or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly., It will be understood that the scope ofcombinations of the compounds of this invention with other agents usefulfor treating atrial fibrillation and atrial flutter includes inprinciple any combination with any pharmaceutical composition useful fortreating atrial fibrillation and atrial flutter.

The compounds of formulae I and II can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powder, granules,elixirs, tinctures, suspensions, syrups and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, topical (e.g., skin cream or ocular eyedrop),subcutaneous, intramuscular, or transdermal (e.g., patch) form, allusing forms well known to those of ordinary skill-in the pharmaceuticalarts.

The dosage regimen utilizing these compounds is selected in accordancewith a variety of factors including type, species, age, weight, sex, andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or salt thereof employed. Anordinarily skilled physician, veterinarian or clinician can readilydetermine and prescribe the effective amount of the drug required toprevent, counter or arrest the progress of the condition.

Oral dosages of the compounds, when used for the indicated effects, willrange between about 0.01 mg per kg of body weight per day (mg/kg/day) toabout 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day(mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day.For oral administration, the compositions are preferably provided in theform of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0,15.0, 25.0, 50.0, 100, and 500 milligrams of the active ingredient forthe symptomatic adjustment of the dosage to the patient to be treated. Amedicament typically contains from about 0.01 mg to about 500 mg of theactive ingredient, preferably from about 1 mg to about 100 mg of activeingredient. Intravenously, the most preferred doses will range fromabout 0.1 to about 10 mg/kg/minute during a constant rate infusion.Advantageously, compounds of the present invention may be administeredin a single daily dose, or te total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, preferredcompounds for the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using those forms of transdermal skin patches will known tothose of ordinary skill in the art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The specific compounds of formulae I and II described herein can formthe active ingredient, and are typically administered in admixture withsuitable pharmaceutical diluents, exipients or carriers (collectivelyreferred to herein as “carrier” materials) suitably selected withrespect to the intended form of administration, that is, oral tablets,capsules, elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms includes sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include without limitation starch, methylcellulose, agar,bentonite, xanthan like.

The compounds of formulae I and II can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as1,2-dipalmitoylphosphatidylcholine, phosphatidyl ethanolamine(cephalin), or phosphatidylcholine (lecithin).

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

The term “alkyl” as employed herein refers to those groups of thedesignated number of carbon atoms in either a straight and branchedchain hydrocarbons, such as methyl, ethyl, propyl, iso-propyl, butyl,isobutyl, tert-butyl, pentyl, hexyl, 2-methylpentyl, and the like.

The term “alkoxy” as employed herein refers to a straight or branchedchain radical attached through an oxygen linkage, containing 1, 2, 3 or4 carbon atoms in the normal chain. Examples of such alkoxy groups aremethoxy, ethoxy, propoxy, butoxy, isobutoxy and the like.

The compounds of formulae I and II can be present as salts, inparticular pharmaceutically acceptable salts. If they have, for example,at least one basic center, they can form acid addition salts. These areformed, for example, with strong inorganic acids, such as mineral acids,for example sulfueric acid, phosphoric acid or a hydrohalic acid, withstrong organic carboxylic acids, such as alkanecarboxylic acids of 1 to4 carbon atoms which are unsubstituted or substituted, for example, byhalogen, for example acetic acid, such as saturated or unsaturateddicarboxylic acids, for example oxalic, malonic, succinic, maleic,fumaric, phthalic or terephthalic acid, such; as hydroxycarboxylicacids, for example ascorbic, glycolic, lactic, malice, tartaric orcitric acid, such as amino acids, for example aspartic or glutamic acidor lysine or arginine), or benzoic acid, or with organic sulfonic acids,such as (C₄-C₄)-alkyl- or aryl-sulfonic acids which are unsubstituted orsubstituted for example by halogen, for example methane- orp-toluene-sulfonic acid. Corresponding acid addition salts can also beformed having, if desired, an additionally present basic center. Thecompounds of formulae I and II having at least one acid group (forexample COOH) can also form salts with bases. Suitable salts with basesare, for example, metal salts, such as alkali metal or alkaline earthmetal salts, for example sodium, potassium or magnesium salts, or saltswith ammonia or an organic amine, such as morpholine, thiomorpholine,piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, forexample ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-,tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy loweralkylamine, for example mono-, di- or triethanolamine. Correspondinginternal salts may furthermore be formed. Salts which are unstable forpharmaceutical uses but which can be employed, for example, for theisolation or purification of free compounds or their pharmaceuticallyacceptable salts are also included.

Preferred salts of the compounds of formulae I and II which include abasic group include monohydrochloride, hydrogensulfate, tartrate,fumarate or maleate. Preferred salts of the compounds which include anacid group include sodium, potassium and magnesium salts andpharmaceutically acceptable organic amines.

The compounds of formulae I and II may contain one or more chiralcenters and therefore may exist as optical isomers. The inventiontherefore comprises the optically inactive racemic (rac) mixtures (a oneto one mixture of enantiomers), optically enriched scalemic mixtures aswell as the optically pure individual enantiomers. The compounds in theinvention also may contain more than one chiral center and therefore mayexist as diastereomers. The invention therefore comprises individualdiastereomers as well as mixtures of diastereomers in cases where thecompound contains more than one stereo center. The compounds in theinvention also may contain acyclic alkenes or oximes and therefore existas either the E (entgegen) or Z (zusammen) isomers. The inventiontherefore comprises individual E or Z isomers as well as mixtures of Eand Z isomers in cases where the compound contains an, acylic alkene oroxime functional group. Also included within the scope of the inventionare polymorphs, hydrates; and solvates of the compounds of the instantinvention.

The present invention includes within its scope prodrugs of thecompounds of formulae I and II. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into, the required compound. Thus, in themethods of treatment of the present invention, the term “administering”shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example in “Design of Prodrugs” ed. H. Bundgaard,Elsevier, 1985, which is incorporated by reference herein in itsentirety. Metabolites of the compounds includes active species producedupon introduction of compounds of this invention into the biologicalmilieu.

The novel compounds of formula I can be prepared according to thefollowing schemes and non-limiting examples, using appropriate materialsand are further exemplified by the following non-limiting specificexamples. The examples further illustrate details of the preparation ofcompounds of formula I. Those skilled in the art will readily understandthat known variation of the conditions and processes of the followingpreparative procedures can be used to prepare these compounds.

The compounds of formula I are prepared according to the general methodsoutlined in Schemes 1 and 2, and according to the methods described.Examples of reagents and procedures for these reactions appearhereinafter and in the working examples.

Compounds of formula I of the invention where X is a carbonyl group(C═O), R₂ is hydrogen, and where variations can be introduced at the R₁,R₃, R₄ and R₅ positions can be prepared using the method outlined belowand indicated in Scheme 1 Examples 1 and 2). In the method, benzofuran 1is regioselective acylated at the β-position by an acyl chloride 2 inthe prescence of a Lewis catalyst such as tin tetrachloride, to give thecoupled material 3 after standard work-up. A huge collection ofdifferent methods for the acylation of aromatics is available in theliterature (see for example: Jerry Mach in Advanced Organic Chemistry,4th ed, 1992, John Wiley & Sons, Inc, p 539-542 and references citedtherein), several of which could be applied in the present method.

The methyl ether function can be removed by treatment of 3 with 1-2equivalents of a Lewis acid such as boron tribromide at low temperatureand in an inert solvent such as dichloromethane or benzene. The reactionmixture gives after standard work-up and purification, the end product4. Several alternative methods for demethylation of anisol derivativesare available in the literature, some which might be applied for theconversion of 3 to 4. Examples of such alternative methods include theuse of: (i) AlBr₃/ethanethiol, Node Manubu et al, Tetrahedron Lett.,1989; (ii) BF₃/dimethyl sulfide, Bindal R. D., Katzenellenbogen J. A.,J. Oig. Chem, 1987, pp 3181; (iii) HBr/acetic acid, Takeshita Hitosh,Bull. Chem. Soc. Jpn., 1986, pp 1125; and the like.

The phenol 4 is finally O-alkylated employing the appropriate halide inthe presence of a base such as potassium carbonate and then furthertreated with a base, to give the end product containing a carboxymethoxyfunction. Several alternative methods for the O-alkylation of phenolsand hydrolysis of carboxylic acid esters have been published in thelitterature, several which might be applied for the conversion of 4 to5.

Compounds of formula I of the invention where X is a methylene group(—CH₂—) is hydrogen and where variation can be introduced at the R₁, R₃,R₄, and R₅ positions can be prepared using the method outlined below andindicated in Scheme 2 (Examples 3 and 4). In the method, the carbonylgroup (C═O) of 3 is reduced to a methylene group (—CH₂—) employing acombination of lithium aluminum hydride and aluminium trichloride asreducing agent. Several other methods for the reduction of carbonylgroups to methylene groups are known in the litterature and might beused here with successful results and are well known to those skilled inthe art (see for example: Jerry March in Advanced Organic Chemistry, 4thed, 1992, John Wiley & Sons, Inc, p 1209-1211 and references citedtherein). The reaction mixture yields after standard work-up thecorresponding reduced material 7, which can be further reacted furtherto give the carboxymethoxy 8 using the same method as described above.

EXAMPLES

The following Examples represent preferred compounds of formula I of thepresent invention. However, they should not be construed as lining theinvention in any way. The following abbreviations, reagents, expressionsor equipment, which are amongst those used in the descriptions below,are explained as follows: gas chromathography mass spectroscopy (GC-MS),electron impact (EI); liquid chromathography mass spectroscopy (LC-MS),electrospray (ES), ethyl acetate (EtOAc).

Example 1 2-methyl-3-(3,5-diisopropyl-4-hydroxybenzoyl)benzofuran (E1)

(a) A stirred mixture of 3,5-diisopropyl-4-methoxybenzoic acid (5 mmol,1.2 g) and phosporous pentachloride (1.3 g, 6.0 mmol) in dichloromethane(50 mL) was refluxed for two hours. The reaction mixture was cooled downto room temperature, 2-methylbenzofuran (0.76 g, 5 mmol) was addedfollowed by tin tetrachloride (1.3 g, 5 mmol). After two hours theorganic solvent was removed and the residue solved in EtOAc, washed withhydrochloric acid (2 N), sodium hydroxide (1 N) and finally with anaqueous saturated solution of sodium chloride. The organic phase wasdried over magnesium sulphate. The crude product was purified on column(silica gel, petrolium ether/EtOAc 9:1) to give 1.7 g (97%) of2-methyl-3-(3,5-diisopropyl-4-methoxybenzoyl)benzofuran as a colorlessoil, which slowly solidified at room temperature: ¹H NMR (CD₃COCD₃) d1.22 (d, 12H, CHCH₃, J=6.9), 2.50 (s, 3H, CH₃), 3.82 (s, 3H, OCH₃),7.24-7.56 (m, 4H, aromatics), 7.65 (s, 2H, H-2′ and H-6′); MS (ES) m/z351 (M−1). (b) A stirred solution of2-methyl-3-(3,5-diisopropyl-4methoxybenzoyl)benzofuran (1.7 g, 4.8 mmol)in 20 mL of dichloromethane was kept under nitrogen and cooled to =40°C. To the solution was added boron tribromide (6.0 mL, 1 N, solution indichloromethane) and left at room temperature over night. The reactionmixture was treated with cold hydrochloric acid (1 N), the phases wereseparated and the organic phase was washed once with water. The organicphase was dried over magnesium sulphate, filtrated and concentrated. Theresidue was subjected to column (silica gel, petrolium ether/EtOAc 8:1)to give 2-methyl-3-(3,5-diisopropyl-4-hydroxybenzoyl)benzofuran as apale yellow crystal mass (1.3 g, 81%): ¹H NMR (Acetone-d6) d 1.21 (d,12H, CHCH₃, J=6.9), 2.51(s, 3H, CH₃), 3.41 (m, 1H, CH), 7.57-7.21 (m,4H, aromatics), 7.64 (s, 2H, H-2′ and H-6′); GC-MS (EI, 70 eV) m/z 336(M⁺).

Example 2 2-Methyl-3-(3,5-diisopropyl-4-carboxymethoxybenzoyl)benzofuran(E2).

A mixture of 2-methyl-3-(3,5-diisopropyl-4benzofuran (170 mg, 0.5 mmol)and K₂CO₃ (138 mg, 1 mmol) in dry acetone (10 mL), a-bromethylacetate(170 mg, 1 mmol) was added during 5 minutes, the solutionwas stirred over night at room temperature. Ethyl acetate was added andthe solution was washed with water. The organic phase was evaporated todryness and the residue was dissolved in a mixture of methanol (2 mL)and sodium hydroxide (2 mL, 1 N). The solution was stirred at roomtemperature over night, extracted with ethyl acetate and dried overmagnesium sulphate. Evaporation of the organic phase gave 1.1 g whichwas purified on column (silica gel, chloroform/methanol/acetic acid95:5:1): ¹H NMR (CD₃COCD₃) d 1.21 (d, 12H, CHCH₃, J=6.9), 2.50 (s, 3H,CH₃), 3.49 (m, 1H, CH), 4.56 (s, 2H, CH₂), 7.21-7.61 (m, 4H, aromatics),7.66 (s, 2H, H-2′ and H-6′); LC-MS (ES) m/z 393(M⁺⁻1).

Example 3 2-Methyl-3-(3,5-diisopropyl-4-hydroxybenzyl)benzofuran (E3)

Aluminium trichloride (120 mg, 4 mmol) in diethyl ether (1.5 mL) wasadded to a suspension of lithiumaluminiumhydride (40 mg, 2 mmol) indiethyl ether (1 mL) during 20 minutes at 0° C.2-Methyl-3-(3,5-diisopropyl-4-hydroxybenzoyl)benzofuran (330 mg, 1 mmol)in 3 mL of ether was added, and the mixture then stirred at roomtemperature for two hours. Excess of the reagent was destroyed b addingwater (1 mL) and sodium hydroxide (0.1 mL). Ethyl acetate (100 mL) wasadded, and the organic layer was washed with sodium bicarbonate anddried over magnesium sulphate. The organic phase was evaporated and theresidue and purified on column (petrolium ether/EtOAc 9:1) to give 290mg (90%) of 2-methyl-3-(3,5-diisopropyl-4-hydroxybenzyl)benzofuran as ared oil: GC-MS (EI, 70 eV) m/z (%) 322(M⁺).

Example 4 2-Methyl-3-(3,5diisopropyl-4-carboxymethoxybenzyl)benzofuran(E4)

This compound was prepared from2-methyl-3-(3,5-diisopropyl-4-hydroxybenzyl)benzofuran (290 mg, 1mmol)and a-brom ethylacetate (230 m, 40.5 mmol), using the proceduredescribed in Example 2. The crude product was purified column(chloroform/methanol/acetic acid 95:5:1) to give 300 mg (79%) of2-methyl-3-(3,5-diisopropyl-4-carboxymethoxy-benzyl)benzofuran as awhite crystal mass: ¹H NMR (CD₃COCD₃) d 1.15 (d, 12H, CHCH₃, J=6.9),2.46 (s, 3H, CH₃), 3.34(m, 1H, CH), 3.97 (s, 2H, CH₂), 4.37(s 2H, CH₂),7.05-7.45 (m, 4H, aromatics), 7.10(s, 2H,H-2′ and H-6′); LC-MS (ES) m/z379(M⁺-−1).

The following Table 1 illustrates the potency (IC50-values) of compoundsof formulae I and II compared with other anti-arrhythmic drugs toinhibit the transmembrane currents IK(Ado) and IK(ACh) after stimulationof the currents with Adenosine or Acetylcholine (or Carbachol). TABLE 1Potency (IC50-values) of compounds of the invention and otheranti-arrhythmic drugs to inhibit the transmembrane currents IK (Ado) andIK (ACh) after stimulation of the currents with Adenosine orAcetylcholine (or Carbachol). IC50: Molar concentration of a compound atwhich 50% inhibition of the induced activity occurs. Inhibition of IK(ACh) Inhibition of IK (Ado) (Induced by ACh or Compound Induced byAdenosine Carbachol) d,l-sotalol (Mori) No effect   36 μM (IC50)Propranolol (Brandts) 8 μM (IC50)   56 μM (IC50) E-4031 (Mori) Someeffect at 100 μM   8 μM (IC50) MS-551 (Mori) Some effect at 100 μM   11μM (IC50) Aprinidine (Ohmoto) Not studied  0.4 μM (IC50) Amiodarone(Watanabe) 2 μM (IC50)   2 μM (IC50) Terikalant (Brandts) 2 μM (IC50)  2 μM (IC50) SUN 1165 (Inomata) Not studied   29 μM (IC50) Flecainide(Inomata) Not studied  3.6 μM (IC50) Disopyramide (Inomata) Not studied 1.7 μM (IC50) Quinidine (Inomata) Not studied  1.6 μM (IC50)Dronedarone Not studied 0.01 μM (IC50) (Guillemare) E5 1 μM (IC50)   1μM (IC50) E6 Similar to E5 Similar to E5 (100% Inh at 50 μM) (100% Inhat 50 μM) E4 100% Inh at 50 μM 100% Inh at 50 μMIC50: Molar concentration of a compound at which 50% inhibition of theinduced activity occurs.E5 is 2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran. (Formula II)E6 is 2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran.(Formula II)E4 is 2-methyl-3-(3,5-diisopropyl-4-carboxymethoxybenzyl)benzofuran.(Formula I)For references, see Table 2.

TABLE 2 Comparison of blocking activity of E4 and E6 and otherantiarrhythmic drugs on different transmembrane ion-currents. IK(Ado)IK(ACh) IK(ATP) IK1 IKs Ito INa E4, E6 Yes Yes Yes No No No No QuinidineU Yes Yes No No Yes Yes (Inomata) (Undrovi) (Slawsky) (Lai) (Slawsky)(Slawsky) Flecainide U Yes Yes No No Yes Yes (Inomata) (Sato) (Slawsky)(Wang) (Slawsky) (Konzen) Disopyramide U Yes Yes No Yes Yes Yes(Inomata) (Wu) (Sato) (Sato) (Sato) (Sato) Aprinidine U Yes U No No YesYes (Ohmoto) (Ohmoto) (Ohmoto) (Tanaka) (Ohmoto) Terikalant Yes Yes NoYes Yes Yes No (RP58866) (Brandts) (Brandts) (Brandts) (Yang) (Yang)(Yang) (Yang) d,l-Sotalol No Yes (Mori) U Yes No Yes No (Mori) (Berger)(Lai) (Berger) (Malecot) Amiodarone Yes Yes Yes Yes Yes U Yes (Watanabe)(Watanabe) (Holmes) (Kodama) (Kodama) (Kodama) Dronedarone U Yes U U YesU Yes (Guillemare) (Guillemare) (Guillemare) Explanations Yes: Thecompound has been demonstrated to inhibit the particular current(reference within parenthesis). No: The compound has been demonstratedto not inhibit the particular current (reference within parenthesis). U:No data regarding interaction of the compound with the particularcurrent has been found in the literature. IK(Ado): Adenosine activatedK-current IK(ACh): AcetylCholine activated K-current IK(ATP):ATP-sensitive K-current IK1: Inward rectifier K-current IKs: Slowcomponent of the delayed rectifier K-current Ito: Transient outwardK-current INa: Depolarizing Na-currentTable 2 References:

-   Inomata N. et al. Br J Pharmacol 1991 December;104(4):1007-11.-   Guillemare E. et al. Marion A, Nisato D, Gautier P. J Cardiovasc    Pharmacol 2000 December;36(6):802-5.-   Undrovinas A I. et al. Am J Physiol 1990 November;259(5    Pt2):H1609-12.-   Slawsky M. T,. And Castle N A. J Pharmacol Exp Ther 1994    April;269(1):66-74.-   Lai L. et al. J Biomned Sci 1999 July-August;6(4):251-9.-   Satoh H Eur J Pharmacol 2000 Oct. 27;407(1-2):123-9.-   Wang D W, et al. Cardiovasc Res 1995 April;29(4):520-5.-   Konzen G. et al. Arch Phmacol 1990 J 341(6:56576-   Wu B. et al. Cardiovasc Res 1992 November;26(11);1095-101.-   Tanaka; H. et al. Naunyn Schmiedebergs Arch Pharmacol 1990    April;341(4):347-56.-   Yang B F. et al. Zhongguo Yao Li Xue Bao 1999 November;20(11):    961-9.-   Berger F. et al. Arch Pharmacol 1989 December;340(6):696-704.-   Holmes D S. Et al. J Cardiovasc Electrophysiol    2000October;11(10):1152-8-   Mori K. et al. Circulation 1995 Jun 1;91(11):2834-43.-   Ohmoto-Sekine Y. et al. Br J Pharmacol 1999 February;126(3):751-61.-   Watanabe Y. et al. J Pharmnacol Exp Ther 1996    November;279(2):617-24.-   Brandts B. et al. Pacing Clin Electrophysiol 2000 November;23(11 Pt    2):1812-5.

1. A compound according to formula I;

wherein: R₁ is C₁-C₄ alkyl; R₂ is NHCOR^(a), NHCONHR^(a), or hydrogen;R₃ and R₄ are independently selected from fluorine, chlorine, C₁-C₆alkyl, and CF₃; R^(a) is selected from CF₃, C₁₋₃ alkyl, and-(4-R^(b))C₆H₄; R^(b) is selected from C₁₋₄ alkoxy, hydroxy, fluoro, andnitro; R₅ is selected from hydrogen and —CH₂—COOH; X is selected fromCH₂ and C═O; with the proviso that when R₅ is hydrogen, X is —CH₂—; andpharmaceutically acceptable salts, esters and isomers thereof.
 2. Acompound according to claim 1 wherein R₂ is hydrogen or NHCOR^(a) andeach of R₃ and R₄ is independently C₁-C₄ alkyl.
 3. A compound accordingto claim 2 wherein R₃ and R₄ are isopropyl.
 4. A compound according toclaim 1 where R₂ is H or NHCOR^(a), and R₅ is —CH₂—COOH.
 5. A compoundaccording to claim 1 wherein R₁ is methyl; R₂ is hydrogen; R₃ and R₄ isC₁-C₄ alkyl; R₅ is —CH₂—COOH; and X is —CH₂—. 6.2-methyl-3-(3,5-diisopropyl-4-hydroxybenzoyl)benzofuran (E1); or2-methyl-3-(3,5-diisopropyl-4-carboxymethoxybenzoyl)benzofuran (E2); or2-methyl-3-(3,5-diisopropyl-4-hydroxybenzyl)benzofuran (E3); or2-methyl-3-(3,5-diisopropyl-4-carboxymethoxybenzyl)benzofuran (E4); orand pharmaceutically acceptable salts, esters and isomers thereof. 7.(Cancelled).
 8. A pharmaceutical composition comprising a compoundaccording to claim 1, together with a pharmaceutically acceptablecarrier.
 9. A method of treating atrial fibrillation or atrial fluttercomprising providing to a patient in need thereof a pharmaceuticallyeffective amount of a compound according to claim
 1. 10-15. (Cancelled).16. A pharmaceutical composition for the treatment of atrialfibrillation or atrial flutter comprising at least one compound thatinhibits certain transmembrane potassium currents, which are more activein the diseased atrium of a mammalian heart than in a normal atrium,without affecting other ion channels.
 17. The composition according toclaim 16, wherein the said inhibition derives from inhibition of one orseveral of the three ligand-gated potassium currents IK(Ado), IK(ACh)and IK(ATP).
 18. The pharmaceutical composition according to claim 16wherein the said inhibition caused by the compound is not due to the T3antagonistic effect.
 19. The pharmaceutical composition according toclaim 16 wherein the compound is a compound according to formula II

wherein: R⁶ is C₁-C₄ alkyl; R⁷ is NHCOR⁵, NHCONHR⁵, or hydrogen; R⁸ andR⁹ are independently selected from iodine and bromine; R₁₀ is selectedfrom CF₃, C₁₋₃ alkyl, and 4-R₆C₆H₄; R¹¹ is selected from C₁₋₄ alkoxy,hydroxy, fluoro, and nitro; R¹² is selected from hydrogen and —CH₂—COOH;X is selected from CH₂ and C═O; or pharmaceutically acceptable salts,esters and isomers thereof.
 20. The pharmaceutical composition accordingto claim 19, wherein the compound is2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran (E5);2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran (E6); orpharmaceutically acceptable salts and esters thereof and isomersthereof.
 21. A method of treating atrial fibrillation or atrial fluttercomprising providing to a patient in need thereof a pharmaceuticallyeffective amount of at least one compound that inhibits certaintransmembrane potassium currents, that are more active in the diseasedatrium of a mammalian heart than in a normal atrium, without affectingother ion channels.
 22. The method according to claim 21, wherein thesaid inhibition derives from inhibition of one or several of the threeligand-gated potassium currents IK(Ado), IK(ACh) and IK(ATP).
 23. Themethod according to claim 21 wherein said inhibition caused by thecompound is not due to the T3 antagonistic effect.
 24. The methodaccording to claim 21 wherein the compound is a compound according toformula II as defined in claim
 14.

wherein: R⁶ is C₁-C₄ alkyl; R⁷ is NHCOR⁵, NHCONHR⁵, or hydrogen; R⁸ andR⁹ are independently selected from iodine and bromine; R¹⁰ is selectedfrom CF₃, C₁₋₃ alkyl, and 4-R₆C₆H₄; R¹¹ is selected from C₁₋₄ alkoxy,hydroxy, fluoro, and nitro; R¹² is selected from hydrogen and —CH₂—COOH;X is selected from CH₂ and C═O; or pharmaceutically acceptable salts,esters and isomers thereof.
 25. The method according to claim 21 whereinthe compound is 2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran(ES); 2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran E6); orpharmaceutically acceptable salts and esters thereof and isomersthereof.